CN109879871A - A kind of raw naphthyridines refining methd of source of phosphoric acid - Google Patents

Abstract

The present invention relates to pharmaceutical technology fields, and in particular to a kind of raw naphthyridines refining methd of source of phosphoric acid.It is mainly used for treating anti-chlorine quinoline strain malignant malaria and rescues the pernicious malarias such as brain type malaria.In the present invention, first that the raw naphthyridines crude product of source of phosphoric acid is soluble in water, active carbon is added, is stirred at room temperature 20 minutes to 1 hour, filters, removes mechanical admixture；Then filtrate is first extracted with organic solvent, discards organic phase, it is between 4~5 that 10% phthalic acid of water phase, which adjusts aqueous solution pH, calcium chloride crystallization is slowly added dropwise again, maintaining crystallization temperature is 15-35 DEG C, and the crystallization time is 2-6h, it filters, obtains white crystal, the as raw naphthyridines of source of phosphoric acid.Method of the invention operates easy, high income, is suitable for industrial-scale production, and the raw naphthyridines product purity of the source of phosphoric acid being prepared is high, can be fully achieved and horizontal higher than Japanese Pharmacopoeia.

Description

A kind of raw naphthyridines refining methd of source of phosphoric acid

Technical field

The present invention relates to pharmaceutical technology fields, and in particular to a kind of raw naphthyridines refining methd of source of phosphoric acid.

Background technique

Source of phosphoric acid raw naphthyridines (CGX1321) is WNT pathway inhibitor.Mainly plasmodium erythrocyte stage schizont is killed The effect of going out.With chloroquine without cross-resistance, clinically for treating the subtertian malarias such as anti-chlorine quinoline strain malignant malaria and rescue brain type malaria Disease.

In vivo with carbenicillin comparison result: to mouse infection caused by Pseudomonas aeruginosa (T plants), this product is than carboxylic benzyl Penicillin is 7~10 times strong, but effective not as good as gentamicin；It is then strong by 4~7 to Pseudomonas aeruginosa No19 and supper toxic strain (NC-5) Times；It is 2~15 times strong to Escherichia coli (NIHJ)；It is 8 times strong to pneumobacillus；It is 2 times strong to hemolytic streptococcus.Internal vigor is general Lower than external.This product is oral not to be absorbed, with Binding rate of serum protein height.Be distributed in vivo, with the content in liver, kidney, serum compared with Height is minimum in brain.Excretion pathway is mainly discharged with original shape by bile.This product half-life period is 4.7h when pH2.It is general efficient It is 64%~72%.Allergic reaction occurs much than other penicillin.

With CN101747342, CN 102408437 in the patent of representative, crude product refining process is not described in detail, It in actual operation cannot be thus to obtain the raw three water acid finished product of naphthyridines of the source of phosphoric acid of high-purity.Since the raw naphthyridines of source of phosphoric acid is first A injection amino acid type penicillin introduces N4- methyl-D-asparagic acid on 6 side chains of penicillin parent nucleus, is improving medicine It while object biodynamic in vivo, also changes its and crystallizes isoelectric point, simultaneously because the raw naphthyridines crude product of source of phosphoric acid includes phosphorus Acid source gives birth to naphthyridines finished product, the raw naphthyridines of the source of phosphoric acid with protecting group, the multiple component such as protecting group also taken off.Therefore the prior art In there is still a need for the methods that can be simple and efficient and high-purity extracts the raw naphthyridines of source of phosphoric acid.

Summary of the invention

In view of in the reaction process for sloughing the raw naphthyridines protecting group of source of phosphoric acid in the prior art, protecting group is sloughed not thorough Bottom is easy to include impurity, and it to be suitable for the phosphorus of industrial-scale production that the object of the present invention is to provide a kind of easy, the high incomes of operation The refining methd of the raw naphthyridines of acid source, method of the present invention can be improved product purity, it are fully achieved and is higher than Japan Pharmacopeia is horizontal, and (product purity requires to be more than or equal to 99%, 0.3%) list is miscellaneous to be less than or equal to.

According to the application embodiment, a kind of raw naphthyridines refining methd of source of phosphoric acid is provided, this method includes Following steps:

A) first that the raw naphthyridines crude product of source of phosphoric acid is soluble in water, activated carbon is added, is stirred at room temperature 20 minutes to 1 hour, mistake Filter removes mechanical admixture；

B) then filtrate is first extracted with organic solvent, discards organic phase, 10% phthalic acid of water phase adjusts water-soluble Liquid pH is between 4~5；

C) calcium chloride crystallization is slowly added dropwise again, maintaining crystallization temperature is 15-35 DEG C, and the crystallization time is 2-6h；

D) it filters, obtains white crystal, the as raw naphthyridines of source of phosphoric acid.

According to the another embodiment of the application, wherein mixing time is preferably 30 minutes in step a)；

According to the another embodiment of the application, wherein the organic solvent described in step b) is that art technology is normal Well known solvent, preferably ethyl acetate, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), benzene, toluene, 2- butanone, 2- fourth Alcohol, n-butanol, chloroform, methylene chloride, carbon tetrachloride；Aqueous pH values are preferably 4.2~4.8；

According to the another embodiment of the application, wherein the raw naphthyridines crude product of the source of phosphoric acid is dissolved using pure water, In, the dosage of water is 10~50 times of the raw naphthyridines crude product quality of source of phosphoric acid.

According to the another embodiment of the application, wherein by the way that calcium chloride crystallization is added dropwise, wherein the dosage of calcium chloride Are as follows: 50-100 times of the raw naphthyridines crude product quality of source of phosphoric acid.

According to the another embodiment of the application, wherein the crystallization temperature described in step c) is preferably 25 DEG C.

According to the another embodiment of the application, wherein the crystallization time described in step c) is preferably 4h.

According to the another embodiment of the application, wherein raw three water of the naphthyridines acid of source of phosphoric acid obtained in step d) Purity is greater than 99%, and list is miscellaneous less than 0.3%.

Present inventor is by careful research and a large amount of experiment discovery, for the crude product of this complex system Matter, the slight change of pH directly affect the precipitation of the raw naphthyridines of source of phosphoric acid.In the case where crystallization liquid pH is excessively high (pH >=5.0), produce Product easily form carboxylate and are dissolved in reaction solution and are not easy to be precipitated, in the case where crystallization liquid pH is too low (pH≤4.0), the easy shape of product It also is soluble at ammonium salt and is not easy to be precipitated in reaction solution, instead, a large amount of impurity is easy directly to be precipitated in acid condition, to be difficult Obtain Aspoxicillin trihydrate finished product.

Present inventor removes ester dissolubility by ethyl acetate first in the raw naphthyridines Crystallization Process of research source of phosphoric acid Impurity, then the pH value of accurate adjustment crystallization liquid, reach the best isoelectric point of product crystallization, while passing through the control chlorination processes calcium of crystallization Additional amount improves the yield of product, thus the purification of the raw naphthyridines of the source of phosphoric acid for completing high-purity high-yield.

Specific embodiment

Embodiment 1:

Under room temperature, the raw naphthyridines crude product of 100g source of phosphoric acid is put into 2000ml there-necked flask, 1000ml is then added Pure water adds 10g active carbon, 30min is stirred at room temperature.Filtering, removes mechanical admixture, and (200ml is extracted with ethyl acetate in filtrate × 3) organic phase, is discarded.Water phase is adjusted to pH=4.5 with 10% phthalic acid, then calcium chloride 5KG is slowly added dropwise, and controls temperature It 25 DEG C, stirring and crystallizing 4h, filters, with chlorination calcium eluviation, is drying to obtain the raw naphthyridines 73g of white crystal source of phosphoric acid, yield 73% is pure Degree 99.6%, single miscellaneous 0.18%.

Embodiment 2:

Under room temperature, the raw naphthyridines crude product of 100g source of phosphoric acid is put into 2000ml there-necked flask, 1000ml is then added Pure water adds 10g active carbon, 30min is stirred at room temperature.Filtering, removes mechanical admixture, and (200ml is extracted with ethyl acetate in filtrate × 3) organic phase, is discarded.Water phase is adjusted to pH=4.5 with 10% phthalic acid, then calcium chloride 10KG is slowly added dropwise, and controls temperature It 25 DEG C, stirring and crystallizing 4h, filters, with chlorination calcium eluviation, is drying to obtain the raw naphthyridines 81g of white crystal source of phosphoric acid, yield 81% is pure Degree 99.1%, single miscellaneous 0.19%.

Claims (2)

1. a kind of raw naphthyridines refining methd of source of phosphoric acid, method includes the following steps:

A) first that the raw naphthyridines crude product of source of phosphoric acid is soluble in water, activated carbon is added, is stirred at room temperature 20 minutes to 1 hour, filters, removes Remove mechanical admixture；

B) then filtrate is first extracted with organic solvent, discards organic phase, water phase adjusts aqueous solution pH with 10% phthalic acid Between 4~5；

C) calcium chloride crystallization is slowly added dropwise again, maintaining crystallization temperature is 15-35 DEG C, and the crystallization time is 2-6h；

D) it filters, obtains white crystal, the as raw naphthyridines of source of phosphoric acid.

2. according to the method described in claim 1, mixing time is 30 minutes wherein in step a).